(-)-Galanthamine and derivatives thereof are useful compounds for the treatment of Alzheimer's disease and related illnesses. Currently galanthamine is usually obtained by extraction from natural sources, such as daffodil or snowdrop bulbs. However, the yields of these extractive procedures are low, resulting in high costs and limited supplies of naturally obtained galanthamine.
It is known that single enantiomer galanthamine (2) can be prepared from racemic narwedine (1) through resolution followed by reduction of the enone function, as depicted in Scheme 1, below. Usefully, since the enantiomers of narwedine (1) readily equilibrate (racemise) by way of reversible ring opening to a dienone, coupled to the fact that crystals of racemic (1) exist as a conglomerate of enantiomers, a dynamic resolution of (1) can be carried out by crystallisation with entrainment by crystals of the desired isomer (see Barton and Kirby, J. Chem. Soc. (C) (1962) 806). However, in respect of a total synthesis, racemic narwedine itself is not readily available. ##STR1##
Several procedures have been developed for the resolution of galanthamine. One procedure involves formation of a diastereomeric salt with di-p-toluoyl tartaric acid and separation of the mixture by recrystallisation; see Kametani et al, Heterocycles, 1976, 1111. However, the need for the unnatural form of tartaric acid to access the desired, therapeutically-active, (-)-galanthamine renders this process costly.
Another resolution procedure involves the formation of diastereomeric esters with (-)-camphanic chloride and separation of the mixture by recrystallisation; see Szewczyk et al, J Het. Chem. (1995) 32: 195. The resultant product is then converted into (-)-galanthamine by reduction in a process which destroys the chiral auxiliary group, so rendering this process impractical for economic production.